The present invention relates to electrospun elements having a continuous or stepwise gradient of porosity, average pore size, weight-per-volume and/or agents attached to, embedded or impregnated therein which can be used as medical membranes and scaffolds for guided tissue regeneration, repair and/or implant.
Tissue regeneration, repair and/or implant are used in treating damaged, traumatized, abnormal functioning, diseased and/or dysfunction tissues. Tissue repair and/or regeneration are based on transplanting scaffolds, membranes or matrices along with cells which are capable of growing into and repairing damaged or diseased tissues. Desired scaffolds, membranes or matrices for tissue regeneration are biocompatible and/or biodegradable materials capable of supporting the growth and/or regeneration of soft or hard tissues. Such substances should therefore be compatible with the desired cure.
Due to their wide acceptance as safe and efficient substances, homologous or heterologous tissue-derived materials such as Collagen, fibronectin, chitosan and alginate are conventionally used for tissue regeneration. However, the use of tissue-derived materials can lead to undesirable immunological rejections, blood coagulation and/or tissue hypertrophy.
On the other hand, artificial tissue made of alloplastic, non-degradable synthetic polymers such as polyethylene glycol (PEG), Hydroxyapatite/polycaprolactone (HA/PCL), polyglycolic acid (PGA), Poly-L-lactic acid (PLLA), Poly lactic co glycolide (PLGA), Polymethyl methacrylate (PMMA), polyhydroxyalkanoate (PHA), poly-4-hydroxybutyrate (P4HB), polypropylene fumarate (PPF), polyethylene glycol-dimethacrylate (PEG-DMA), beta-tricalcium phosphate (beta-TCP) and non biodegradable polytetrafluoroethylene (PTFE) poly-anhydrides, poly-phosphazenes, poly-tetrafluoroethylene (PTFE), and PMMA/polyhydroxyethylmethacrylate (PHEMA) display excellent physical properties including the precise control over the material mechanical properties. However, such synthetic scaffolds lack sufficient bioaffinity and compatibility, homeostatic regulation and many specific cell interactions which regulate cell proliferation and organization.
To overcome such limitations, various hormones, growth factors and extracellular matrix components were either impregnated, mixed or cross-linked to the scaffold backbone. However, such modifications failed sometimes to provide sufficient biological signals which guide cell growth and differentiation.
Bone repair is one of the major challenges for orthopedic medicine. Bone and teeth are molecular composites of inorganic hydroxyapatite and collagen which are arranged in a three-dimensional matrix. Thus, common materials used for hard tissue repair are based on biocompatible ceramics formed on matrix surface having high strength (e.g., a metal matrix), native polymers and/or extracellular matrix proteins, such as Collagen. Collagens, comprise a majority of proteins in connective tissue such as skin, bone, cartilage and tendons.
Biodegradable polymers such as polycaprolacton (PCL), polylactic acid (PLA), polyglycolic acid (PGA), their blends and copolymers exhibit high molecular weight structures which, following hydrolysis or other biologically derived processes, can be break down to less complicated, smaller and soluble molecules. Such degradation can occur under the action of living organisms (e.g., bacteria) or by the various processes in the body, including biochemical and non-enzymatic chemical degradation.
Biodegradable hydrogel scaffolds made of various biodegradable polymers (e.g., collagen based hydrogel) were found suitable for growth and differentiation of bone marrow derived mesenchymal stem cells (MSCs). In addition, enhanced bone defect repair was achieved in hydrogel scaffolds impregnated with growth factors. Other PCL-based polymers or copolymers scaffolds were reported to provide biocompatible structures for both osteogenesis (Yoshimoto et al. 2003) and chondrogenesis (Li et al., 2003; 2005; Tuli et al., 2004). However, although hydrogel scaffolds are biodegradable and capable of promoting cell differentiation in vitro, their relatively small porosity and low strength prevent their use in clinical applications such as bone repair.
Recently, Collagen, PLLA, PLGA, PCL, their blends and copolymers scaffolds were fabricated using electro-spinning (see for example, U.S. Pat. Appl. No. 20040037813 to Simpson David G, et al; Lee Y H, et al., 2005, Biomaterials. 26: 3165-72; Khil M S, et al., 2005, J. Biomed. Mater. Res. B Appl Biomater. 72: 117-24; Li et al., 2002; Yoshimoto et al., 2003). Electro-spinning is a process that uses an electrostatic field to control the formation and deposition of polymers. This process is remarkably efficient, rapid, and inexpensive. In electro-spinning, a polymer solution or melt is charged with an electrostatic potential to create a charge imbalance and then is injected through a needle of a syringe to a grounded target. At a critical voltage, the charge repulsion begins to overcome the surface tension of the polymer drop, extruding an electrically charged jet. The jet within the electrostatic field is directed towards the grounded target, during which time the solvent evaporates and fibers are formed. Electro-spinning produces a single continuous nano to micro-fibrous filament which is collected by the grounded target as a non-woven fabric (Theron A, et al., 2001). Notably, it is possible to fabricate filaments on the nanometer scale using this technique for in-vivo guided tissue regeneration and or repair. However, the presently available electrospun scaffolds are not suitable for in vivo guided tissue regeneration and/or repair.